EP300-Mediated MTF1-K218 Lactylation Buffers AR-Driven Copper Overload to Suppress Cuproptosis in Castration-Resistant Prostate Cancer

  • Adv Sci (Weinh). 2026 Aug 11:e77110. doi: 10.1002/advs.77110.
Kai Li  1 ,  Yong Wei  1 ,  Yongshan Li  1 ,  Yuxiang Dong  1 ,  Jiancheng Lv  2 ,  Mingzhi Yuan  3  4  5 ,  Ao Shen  4  5 ,  Fuyang Liu  1 ,  Yetao Zhang  1 ,  Youjian Li  1 ,  Ruixi Yu  6 ,  Yang Liu  7 ,  Tong Zhao  1 ,  Jun Wang  1 ,  Kai Zhou  8 ,  Zongyao Fan  1 ,  Manning Wang  4  5 ,  Jun Xu  3 ,  Mulong Du  1  9 ,  Min Gu  1 ,  Bing Yao  10  11 ,  Qingyi Zhu  1
Affiliations
  • 1. Department of Urology, Jiangsu Key Laboratory of Urological Disease Prevention and Treatment, The Second Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China.
  • 2. Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 3. Jiangsu Key Laboratory of Intelligent Medical Image Computing, School of Artificial Intelligence, Nanjing University of Information Science and Technology, Nanjing, China.
  • 4. Digital Medical Research Center, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 5. Shanghai Key Laboratory of Medical Image Computing and Computer Assisted Intervention, Fudan University, Shanghai, China.
  • 6. Department of Urology, Jiangnan University Medical Center, Wuxi, China.
  • 7. Department of Pathology, Wuxi People's Hospital, Wuxi, China.
  • 8. Department of Urology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 9. Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
  • 10. National Experimental Teaching Center of Basic Medical Science, Department of Medical Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
  • 11. State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, NHC Key Laboratory of Antibody Technique, Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing Medical University, Nanjing, China.
PMID: 42579622 DOI: 10.1002/advs.77110
Abstract

Inducing Cuproptosis for Cancer therapy currently relies on supraphysiological copper or copper ionophores. Although serum copper is elevated in patients with Prostate Cancer, whether this is sufficient to trigger physiological Cuproptosis remains unclear. Here, we show that tumor copper levels positively correlate with Androgen Receptor (AR) activity, and Castration-Resistant Prostate Cancer (CRPC) with hyperactivated AR exhibits pathological copper accumulation. AR activation enhances copper uptake while simultaneously conferring tolerance to copper toxicity, creating a buffered copper state. This adaptive response is mediated by metal-responsive transcription factor 1 (MTF1), which is transcriptionally upregulated by AR and undergoes EP300-dependent lactylation of lysine 218, promoting copper-induced nuclear translocation. Nuclear MTF1 activates metallothioneins (MT1E, MT1F, and MT1M) that sequester cytosolic copper and restrict mitochondrial copper accumulation. Disrupting MTF1 collapses this buffering system, enabling endogenous copper to trigger Cuproptosis and suppress CRPC growth. These findings identify Cuproptosis as a therapeutically exploitable vulnerability in CRPC.

Keywords
androgen receptor; cancer research; copper; copper toxicity; cytosol; downregulation and upregulation; metallothionein; mitochondrion; prostate cancer; transcription factor.
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